Disruptive innovation.
Top Line: Primary CNS lymphoma (PCNSL) is almost exclusively a CD20(+) diffuse large B-cell lymphoma (DLBCL), so treating it with the monoclonal anti-CD20 antibody rituximab just makes sense.
The Study: Rituximab is a standard backbone of therapy for most DLBCL, but it is also a very large molecule with questionable CNS penetration. Treatment of PCNSL typically consists of high-dose methotrexate followed by additional therapy depending on response. In the HOVON 105 trial, patients with PCNSL were treated with an induction methotrexate regimen +/- rituximab. Responders (86% across both arms) then received consolidative cytarabine, with those <60 years of age also receiving whole brain radiation of 30 Gy in 20 fractions with a simultaneous boot to 40 Gy to any residual disease. Unfortunately, the primary endpoint of event-free survival (EFS) at one year was 50% in both arms. Interestingly, though, an unplanned subset analysis among those <60 (and therefore receiving radiation) demonstrated a huge spread in median EFS from 20 to 60 months without and with rituximab. This generated the hypothesis that radiation-induced disruption of the blood brain barrier may enhance CNS penetration of circulating rituximab—a monoclonal antibody that's otherwise not going anywhere anytime soon.
Bottom Line: Adding rituximab to high-dose methotrexate for PCNSL does not improve EFS across the board, but it did indicate intriguing long-term responses among patients receiving consolidative radiation. | Bromberg, Lancet Oncol 2019
The Study: Rituximab is a standard backbone of therapy for most DLBCL, but it is also a very large molecule with questionable CNS penetration. Treatment of PCNSL typically consists of high-dose methotrexate followed by additional therapy depending on response. In the HOVON 105 trial, patients with PCNSL were treated with an induction methotrexate regimen +/- rituximab. Responders (86% across both arms) then received consolidative cytarabine, with those <60 years of age also receiving whole brain radiation of 30 Gy in 20 fractions with a simultaneous boot to 40 Gy to any residual disease. Unfortunately, the primary endpoint of event-free survival (EFS) at one year was 50% in both arms. Interestingly, though, an unplanned subset analysis among those <60 (and therefore receiving radiation) demonstrated a huge spread in median EFS from 20 to 60 months without and with rituximab. This generated the hypothesis that radiation-induced disruption of the blood brain barrier may enhance CNS penetration of circulating rituximab—a monoclonal antibody that's otherwise not going anywhere anytime soon.
Bottom Line: Adding rituximab to high-dose methotrexate for PCNSL does not improve EFS across the board, but it did indicate intriguing long-term responses among patients receiving consolidative radiation. | Bromberg, Lancet Oncol 2019
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